Inotersen (Tegsedi)
Hereditary transthyretin amyloidosis (hATTR) is a progressive, life-threatening disease caused by mutations in the TTR gene, which encodes transthyretin — a protein produced primarily in the liver that normally transports thyroxine and retinol-binding protein in the blood. Mutations destabilize the transthyretin tetramer, causing misfolded monomers to aggregate into amyloid fibrils that deposit in tissues throughout the body, particularly in peripheral nerves and the heart.
The clinical presentation varies by mutation but typically includes progressive polyneuropathy (numbness, pain, and weakness in the extremities), autonomic dysfunction, and cardiomyopathy. The Val30Met mutation is the most common worldwide, though over 130 different pathogenic TTR mutations have been identified. Without treatment, hATTR is fatal, with a median survival of 7–12 years after symptom onset depending on the mutation and phenotype.
Hereditary transthyretin amyloidosis is a gain-of-function disease: the mutant protein actively causes harm through amyloid deposition. This makes it an ideal target for gene-silencing ASO therapy. The strategy is to reduce TTR mRNA levels, thereby reducing production of the misfolded protein and slowing or halting amyloid accumulation.
Inotersen (Tegsedi), approved by the FDA in 2018, is a 2′-O-methoxyethyl (2′-MOE) phosphorothioate gapmer ASO that targets TTR mRNA for RNase H-mediated degradation. The gapmer design features a central DNA gap flanked by 2′-MOE modified wings: the DNA gap recruits RNase H to cleave the target mRNA, while the 2′-MOE wings provide nuclease resistance and binding affinity. Inotersen is administered as a weekly subcutaneous injection and has been shown to reduce serum TTR levels by approximately 75% and slow neuropathy progression.
The gene-silencing mechanism used in hATTR treatment — RNase H-mediated mRNA degradation via gapmer ASOs — is one of the most established ASO strategies. It is also the mechanism behind Tofersen (Qalsody) for ALS and Mipomersen (Kynamro) for familial hypercholesterolemia. The gapmer design is well-characterized, with decades of clinical experience across multiple approved drugs.
Pequliar designs gene-silencing ASO candidates for hATTR and other gain-of-function diseases. While Inotersen targets a region of TTR mRNA common to all mutations, personalized designs can optimize for the specific patient’s sequence context, potentially identifying binding sites with superior thermodynamic properties. The platform generates gapmer ASO candidates with full chemistry assignment, thermodynamic scoring, and off-target screening, delivering synthesis-ready sequences for preclinical evaluation or compassionate use applications.
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Start a designPequliar is a computational research tool for informational purposes only. All sequences are computationally predicted candidates that have not been experimentally validated. Pequliar does not prescribe, recommend, or administer any compound. Independent validation by qualified professionals is required.